Project 2 of our program project proposal is entitled "Gene therapy for bladder pain" (P.I.: Naoki Yoshimura, Department of Urology). This is a preclinical study that will investigate a gene therapy approach in the treatment of visceral pain in the lower urinary tract (LUT). Interstitial cystitis (1C) is a painful bladder syndrome of unknown etiology, characterized by chronic pelvic pain, urinary frequency and urgency. It affects an estimated 450,000 people in the United States. Despite this high incidence the pain-related symptoms in patients with 1C are often very difficult to treat;therefore new therapies are desperately needed for the many sufferers with refractory 1C. In this research project, we propose a novel gene therapy strategy using herpes simplex virus (HSV)-based vectors to treat pain in several rodent models of visceral pain of the LUT. By utilizing the natural biology of HSV, HSV-based vectors can deliver gene products directly to target organ-specific sensory pathways such as those innervating the bladder, urethra, and pelvic floor. We will use two approaches for our treatment strategy. The first will employ HSV vectors containing the proenkaphlin or glutamic acid decarboxylase (GAD) gene in order to increasing the amount of the endogenous opioid peptide enkepahlin or the inhibitory neurotransmitter gamma-amino butyric acid (GABA) within the dorsal horn (DH) of the spinal cord. The second approach will employ HSV vectos containing the anti-inflammatory interleukin-4 (IL-4) or truncated tumor necrosis factor alpha receptor (TNFalphaSR) genes in order to reduce the inflammatory response either in the DH or the target organ. The outcomes of the experiments proposed here we will determine several important issues: (1) HSV-based viral vectors can transfer therapeutic genes to afferent pathways after local injections into the different portions of the LUT, (2) HSV vector-mediated transgene expression in bladder afferent pathways can prevent and/or reverse pain and irritation of the LUT in the different animal models of acute C-fiber sensitization, (3) HSV vector-mediated transgene expression can also have therapeutic effects on nociceptive responses and/or urinary frequency induced by C-fiber hyperexcitability in chronic animal models of tissue inflammation or nerve injury in the LUT. The long-term objectives of the research program are to establish a safe and effective method of gene therapy using HSV vectors carrying therapeutic genes for the treatment of chronic bladder and/or pelvic pain associated with painful bladder syndromes including 1C.